Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation.
Deletion of EP4 on bone marrow-derived cells enhances inflammation and angiotensin II-induced abdominal aortic aneurysm formation.
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DOI：
10.1161/atvbaha.110.216580
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发表时间：
2011-02
期刊：
影响因子：
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通讯作者：
Libby P
中科院分区：
文献类型：
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作者：
Tang EH;Shvartz E;Shimizu K;Rocha VZ;Zheng C;Fukuda D;Shi GP;Sukhova G;Libby P
研究骨髓源性细胞上前列腺素E受体4（EP 4）的缺失是否会增加局部炎症并促进体内腹主动脉瘤（AAA）的形成。前列腺素E2（PGE 2）通过激活其受体EP 4，可以抑制炎症。移植了EP 4 +/+ [EP 4 +/+/LDLR−/−]或EP 4 −/− [EP 4 −/−/LDLR −/−]骨髓的高胆固醇血症低密度脂蛋白受体（LDLR −/−）小鼠接受血管紧张素II输注以诱导AAA。骨髓源性细胞缺乏EP 4可增加（50%的男性EP 4 +/+/LDLR−/−与88.9%的男性EP 4 −/−/LDLR−/−患AAA; 22%的女性EP 4 +/+/LDLR−/−与83.3%的女性EP 4 −/−/LDLR−/−发生AAA）和AAA的严重程度，单核细胞趋化蛋白-1增加（雄性为2.72倍，雌性为1.64倍），巨噬细胞（雄性为3.8倍，雌性为2.44倍）和T细胞（雄性为1.88倍，雌性为1.66倍）向AAA病变的浸润增强。缺乏EP 4的骨髓来源的细胞增强弹性蛋白碎片，增加凋亡标记物，并减少平滑肌细胞积聚在AAA病变。在高脂血症小鼠中，骨髓源性细胞上的EP 4缺乏增强了血管紧张素II诱导的炎症和AAA形成。本研究证实了PGE 2通过EP 4信号传导作为参与实验性动脉瘤形成的内源性抗炎途径的病理生理学重要性。
To examine whether a lack of prostaglandin E receptor 4 (EP4) on bone marrow-derived cells would increase local inflammation and enhance the formation of abdominal aortic aneurysm (AAA) in vivo. Prostaglandin E2 (PGE2), through activation of its receptor EP4, can mute inflammation. Hypercholesterolemic low-density lipoprotein receptor knockout (LDLR−/−) mice transplanted with either EP4+/+ [EP4+/+/LDLR−/−] or EP4−/− [EP4−/−/LDLR−/−] bone marrow received infusions of angiotensin II to induce AAA. Deficiency of EP4 on bone marrow–derived cells increased the incidence (50% of male EP4+/+/LDLR−/− vs. 88.9% male EP4−/−/LDLR−/− developed AAA; and 22% of female EP4+/+/LDLR−/− vs. 83.3% female EP4−/−/LDLR−/− developed AAA) and severity of AAA, increased monocyte chemoattractant protein-1 (2.72-fold in males and 1.64-fold in females), and enhanced infiltration of macrophages (3.8-fold in males and 2.44-fold in females) and T cells (1.88-fold in males and 1.66-fold in females) into AAA lesions. Lack of EP4 on bone marrow–derived cells augmented elastin fragmentation, increased apoptotic markers, and decreased smooth-muscle cell accumulation within AAA lesions. Deficiency of EP4 on bone marrow–derived cells boosted inflammation and AAA formation induced by angiotensin II in hyperlipidemic mice. This study affirms the pathophysiologic importance of PGE2 signaling through EP4 as an endogenous anti-inflammatory pathway involved in experimental aneurysm formation.